Abstract Approximately 90% of deaths due to breast cancer are from metastatic tumor spread to distal organs. Secondary lung metastases are identified in 30-55% of these patients and unfortunately the 5-year survival rate is only 30-40% for surgical resection and chemo-radio treatments. These poor outcomes signify a critical need to further understand the mechanisms impacting tumor metastasis. The long-term goal of our research is to design innovative approaches that increase the immune system's ability to prevent lung tumor metastasis through an increased knowledge of anti-tumor immunity. Current immune-based strategies that implement soluble cytokines and antibodies have been introduced in clinical and pre-clinical trials to broadly boost immune responses against cancers. However, off-target organ damage and immune tolerance has significantly limited their use. Particle-based nanotechnology is emerging as a feasible approach to manipulate immune function. However, we do not fully understand how these components influence immune phenotype and function as a predictor of tumor cell escape and the efficacy of nanoparticle use could benefit improve immune therapy. Based on previous literature findings and our own preliminary findings described in this application, our central hypotheses are: 1) Intranasal administration of CPG bound to the surface of NP-encapsulated tumor antigen induces protective lung mucosal immune protection against secondary lung tumor metastases and 2) Metabolites produced within primary and secondary lung tumor microenvironments dictate tumor immune escape and metastasis. To address our hypotheses, we propose the following two Specific Aims: Aim 1) To determine the efficacy of intranasal delivery of NP-based tumor vaccine as a prophylactic approach against metastatic lung lesions. Aim 2) To establish a metabolomics-based experimental approach used to define primary and metastatic tumor microenvironments. Through this collaborative Pilot Project with Dr. Byron Quinn of Langston University, we expect our findings we shed light of currently unknown mediators of anti- tumor responses that will be potentially useful in the development of novel immune-based targeted nanoparticle in cancer therapy. In addition, we anticipate that this pilot proposal will positively impact the building of a collaborative P20 in Cancer Research between Langston University and its partner, The University of North Texas Health Science Center.